Published Online
on August 9, 2004

A more recent version of this article appeared on August 31, 2004

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Submitted on August 7, 2002
Revised on April 13, 2004
Accepted on April 14, 2004

Angiogenesis and Vasculogenesis Are Impaired in the Precocious-Aging klotho Mouse

Toshifumi Shimada MD, Yoshiaki Takeshita MD, Toyoaki Murohara MD^*, Ken-ichiro Sasaki MD, Kimiyasu Egami MD, Satoshi Shintani MD, Yosuke Katsuda MD, Hisao Ikeda MD, Yo-ichi Nabeshima MD, and Tsutomu Imaizumi MD

From the Cardiovascular Research Institute (T.S., Y.T., T.M., K.-i.S., K.E., S.S., Y.K., H.I., T.I.), Kurume University, Kurume; the Department of Cardiology (T.M.), Nagoya University Graduate School of Medicine, Nagoya; and the Department of Pathology and Tumor Biology (Y.-i.N.), Kyoto University Graduate School of Medicine, Kyoto, Japan.

^* To whom correspondence should be addressed. E-mail: murohara{at}med.nagoya-u.ac.jp.

Background--The effects of aging on angiogenesis (vascular sprouting) and vasculogenesis (endothelial precursor cell [EPC] incorporation into vessels) are not well known. We examined whether ischemia-induced angiogenesis/vasculogenesis is altered in klotho (kl) mutant mice, an animal model of typical aging.

Methods and Results--After unilateral hindlimb ischemia, laser Doppler blood-flow (LDBF) analysis revealed a decreased ischemic-normal LDBF ratio in kl mice. Tissue capillary density was also suppressed in kl mice (+/+>+/kl>kl/kl). Aortic-ring culture assay showed impaired angiogenesis in kl/kl mice, accompanied by reduced endothelium-derived nitric oxide release. Moreover, the rate of transplanted homologous bone marrow cells incorporated into capillaries in ischemic tissues (vasculogenesis) was lower in kl/kl mice than in wild-type (+/+) mice, which was associated with a decrease in the number of c-Kit⁺CD31⁺ EPC-like mononuclear cells in bone marrow and in peripheral blood. Finally, the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor cerivastatin restored the impaired neovascularization in kl/kl mice, accompanied by an increase in c-Kit⁺CD31⁺ cells in bone marrow and peripheral blood, and enhanced angiogenesis in the aortic-ring culture.

Conclusions--Angiogenesis and vasculogenesis are impaired in kl mutant mice, a model of typical aging. Moreover, the age-associated impairment of neovascularization might be a new target of statin therapy.

Key words: aging • angiogenesis • ischemia • statins • vasculature

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